Autophagy , an evolutionarily conserved lysosomal degradation process , has drawn an increasing amount of attention in recent years for its role in a variety of human diseases, such as cancer. Notably, autophagy plays...Autophagy , an evolutionarily conserved lysosomal degradation process , has drawn an increasing amount of attention in recent years for its role in a variety of human diseases, such as cancer. Notably, autophagy plays an important role in regulating several survival and death signaling pathways that determine cell fate in cancer. To date, substantial evidence has demonstrated that some key autophagic mediators, such as autophagy-related genes (ATGs), PI3K, mTOR, p53, and Beclin-1, may play crucial roles in modulating autophagic activity in cancer initiation and progression. Because autophagy-modulating agents such as rapamycin and chloroquine have already been used clinically to treat cancer, it is conceivable that targeting autophagic pathways may provide a new opportunity for discovery and development of more novel cancer therapeutics. With a deeper understanding of the regulatory mechanisms governing autophagy, we will have a better opportunity to facilitate the exploitation of autophagy as a target for therapeutic intervention in cancer. This review discusses the current status of targeting autophagic pathways as a potential cancer therapy.展开更多
Development is a sophisticated process maintained by various signal transduction pathways,including the Hedgehog(Hh)pathway.Several important functions are executed by the Hh signaling cascade such as organogenesis,ti...Development is a sophisticated process maintained by various signal transduction pathways,including the Hedgehog(Hh)pathway.Several important functions are executed by the Hh signaling cascade such as organogenesis,tissue regeneration,and tissue homeostasis,among various others.Considering the multiple functions carried out by this pathway,any mutation causing aberrant Hh signaling may lead to myriad developmental abnormalities besides cancers.In the present review article,we explored a wide range of diseases caused by aberrant Hh signaling,including developmental defects and cancers.Finally,we concluded this mini-review with various treatment strategies for Hh-induced diseases.展开更多
Targeted therapies that deliver the expected anti-tumor effects while mitigating the adverse effects are taking the cancer world by storm. The need for such therapies in non-small cell lung cancer(NSCLC), where system...Targeted therapies that deliver the expected anti-tumor effects while mitigating the adverse effects are taking the cancer world by storm. The need for such therapies in non-small cell lung cancer(NSCLC), where systemic cytotoxic chemotherapies still remain the backbone of management, is felt more than ever before. Runway success of immunotherapies such as Ipilimumab for melanoma has brought excitement among oncologists. Immune-based treatments are in various stages of evaluation for NSCLC as well. Immunotherapies using strategies of antigen based or cell based vaccines, and blocking immune checkpoints are of substantial interest. Meaningful clinical responses are yet to be reaped from these new treatment modalities.展开更多
Accelerated partial breast irradiation (APBI) has been proposed as an alternative to whole breast radiotherapy in select patients undergoing post lumpectomy radiation therapy as part of a breast conserving approach. T...Accelerated partial breast irradiation (APBI) has been proposed as an alternative to whole breast radiotherapy in select patients undergoing post lumpectomy radiation therapy as part of a breast conserving approach. This comprehensive review attempts to assess the current literature and identify appropriate patients as well as supportive data.展开更多
For biliary tract carcinoma(BTC),complete surgical resection of tumor is only feasible in a minority of patients,and the treatment options for patients with unresectable or metastatic disease are limited.Advances in c...For biliary tract carcinoma(BTC),complete surgical resection of tumor is only feasible in a minority of patients,and the treatment options for patients with unresectable or metastatic disease are limited.Advances in cancer immunology have led to identification of tumor-infiltrating immune cells as indicators of prognosis and response to treatment in BTC.This has also facilitated development of immunotherapy that focuses on enhancing the immune system against biliary tumors.This includes peptide- and dendritic cell-based vaccines that stimulate in-vivo immune responses against tumorspecific antigens.Adoptive immunotherapy,which entails the ex-vivo expansion of tumor-infiltrating immune cells for subsequent reintroduction,and cytokinebased therapies have been developed in BTC.Clinical studies indicate that this type of therapy is generally well tolerated.Combination therapy with dendritic cell-based vaccines and adoptive immunotherapy has shown particularly good potential.Emerging strategies through discovery of novel antigen targets and by reversal of tumor-associated immunosuppression are expected to improve the efficacy of immunotherapy in BTC.Collaborative efforts by integration of targeted immunotherapeutics with molecular profiling of biliary tumor will hopefully make a positive impact on advancing towards the goal of developing precision treatment of patients with this highly lethal disease.展开更多
The primary malignancies of the biliary tract, cholangio-carcinoma and gallbladder cancer, often present at an advanced stage and are marginally sensitive to radiation and chemotherapy. Accumulating evidence indicates...The primary malignancies of the biliary tract, cholangio-carcinoma and gallbladder cancer, often present at an advanced stage and are marginally sensitive to radiation and chemotherapy. Accumulating evidence indicates that molecularly targeted agents may provide new hope for improving treatment response in biliary tract carcinoma(BTC). In this article, we provide a critical review of the pathogenesis and genetic abnormalities of biliary tract neoplasms, in addition to discussing the current and emerging targeted therapeutics in BTC. Genetic studies of biliary tumors have identified the growth factors and receptors as well as their downstream signaling pathways that control the growth and survival of biliary epithelia. Target-specific monoclonal antibodies and small molecules inhibitors directed against the signaling pathways that drive BTC growth and invasion have been developed. Numerous clinical trials designed to test these agents as either monotherapy or in combination with conventional chemotherapy have been completed or are currently underway. Research focusing on understanding the molecular basis of biliary tumorigenesis will continue to identify for targeted therapy the key mutations that drive growth and invasion of biliary neoplasms. Additional strategies that have emerged for treating this malignant disease include targeting the epigenetic alterations of BTC and immunotherapy. By integrating targeted therapy with molecular profiles of biliary tumor, we hope to provide precision treatment for patients with malignant diseases of the biliary tract.展开更多
Autophagy, a cellular process of "self-eating" by which intracellular components are degraded within the lysosome, is an evolutionarily conserved response to various stresses. Autophagy is associated with nu...Autophagy, a cellular process of "self-eating" by which intracellular components are degraded within the lysosome, is an evolutionarily conserved response to various stresses. Autophagy is associated with numerous patho-physiological conditions, and dysregulation of autophagy contributes to the pathogenesis of a variety of human diseases including cancer. Depending on context, activation of autophagy may promote either cell survival or death, two major events that determine pathological process of many illnesses. Importantly, the activity of autophagy is often associated with apoptosis, another critical cellular process determining cellular fate. A better understanding of biology of autophagy and its implication in human health and disorder, as well as the relationship between autophagy and apoptosis, has the potential of facilitating the development of autophagy -based therapeutic interventions for human diseases such as cancer.展开更多
Despite various advances in cancer research,the incidence and mortality rates of malignant diseases have remained high.Accurate risk assessment,prevention,detection,and treatment of cancer tailored to the individual a...Despite various advances in cancer research,the incidence and mortality rates of malignant diseases have remained high.Accurate risk assessment,prevention,detection,and treatment of cancer tailored to the individual are major challenges in clinical oncology.Artificial intelligence(AI),a field of applied computer science,has shown promising potential of accelerating evolution of healthcare towards precision oncology.This article focuses on highlights of the application of data-driven machine learning(ML)and deep learning(DL)in translational research for cancer diagnosis,prognosis,treatment,and clinical outcomes.MLbased algorithms in radiological and histological images have been demonstrated to improve detection and diagnosis of cancer.DL-based prediction models in molecular or multi-omics datasets of cancer for biomarkers and targets enable drug discovery and treatment.ML approaches combining radiomics with genomics and other omics data enhance the power of AI in improving diagnosis,prognostication,and treatment of cancer.Ethical and regulatory issues involving patient confidentiality and data security impose certain limitations on practical implementation of ML in clinical oncology.However,the ultimate goal of application of AI in cancer research is to develop and implement multi-modal machine intelligence for improving clinical decision on individualized management of patients.展开更多
Objective and Impact Statement.Simultaneous imaging of ultrasound and optical contrasts can help map structural,functional,and molecular biomarkers inside living subjects with high spatial resolution.There is a need t...Objective and Impact Statement.Simultaneous imaging of ultrasound and optical contrasts can help map structural,functional,and molecular biomarkers inside living subjects with high spatial resolution.There is a need to develop a platform to facilitate this multimodal imaging capability to improve diagnostic sensitivity and specificity.Introduction.Currently,combining ultrasound,photoacoustic,and optical imaging modalities is challenging because conventional ultrasound transducer arrays are optically opaque.As a result,complex geometries are used to coalign both optical and ultrasound waves in the same field of view.Methods.One elegant solution is to make the ultrasound transducer transparent to light.Here,we demonstrate a novel transparent ultrasound transducer(TUT)linear array fabricated using a transparent lithium niobate piezoelectric material for real-time multimodal imaging.Results.The TUT-array consists of 64 elements and centered at~6 MHz frequency.We demonstrate a quad-mode ultrasound,Doppler ultrasound,photoacoustic,and fluorescence imaging in real-time using the TUT-array directly coupled to the tissue mimicking phantoms.Conclusion.The TUT-array successfully showed a multimodal imaging capability and has potential applications in diagnosing cancer,neurological,and vascular diseases,including image-guided endoscopy and wearable imaging.展开更多
Acquired bone marrow failure diseases(ABMFD) are a class of hematopoietic stem cell diseases with a commonality of non-inherited disruption of hematopoiesis that results in pancytopenia. ABMFDs also are a group of het...Acquired bone marrow failure diseases(ABMFD) are a class of hematopoietic stem cell diseases with a commonality of non-inherited disruption of hematopoiesis that results in pancytopenia. ABMFDs also are a group of heterogeneous diseases with different etiologies and treatment options. The three most common ABMFDs are aplastic anemia, myelodysplastic syndrome, and paroxysmal nocturnal hemoglobinuria. Stem cell transplantation is the only treatment that can cure these diseases. However, due to high therapy-related mortality, stem cell transplantation has rarely been used as a first line treatment in treating ABMFD. With the advance of personalized medicine and precision medicine, various novel cellular therapy strategies are in trial to increase the efficiency and efficacy of ABMFD treatment. This article aims to review current available stem cell transplantation protocols and promising cellular therapy research in treating ABMFD.展开更多
Objective To provide a summary of the relationship between the eEF-2/eEF-2 kinase pathway and each phase of malignant neoplasms. The specific importance of this relationship in understanding and treating cancer was al...Objective To provide a summary of the relationship between the eEF-2/eEF-2 kinase pathway and each phase of malignant neoplasms. The specific importance of this relationship in understanding and treating cancer was also explored. Data sources The data used in this review were mainly obtained from the articles listed in HighWire and PubMed in English. The search terms were ＂eEF-2 kinase＂, ＂oncogenesis＂, and ＂tumor progression＂. Study selection This review relates the observation that the overexpression of eEF-2 kinase is seen in cancer, and highlights that it has emerged as promoting the development of many malignant phenotypes when unregulated. This includes increasing the replicative potential of cells, angiogenesis, invasion and metastasis, and evasion of apoptosis. Results eEF-2 kinase is a structurally and functionally unique protein kinase. The increased activity of this protein in cancer cells is a protective mechanism to allow tumor growth and evolution, and resist cell death through the eEF-2/eEF-2 kinase pathway, but it also makes a potential target for therapy. Conclusion eEF-2 kinase fills critical niches in the life of a cancer cell and the eEF-2/eEF-2 kinase pathway is a key biochemical sensor.展开更多
Craniomaxillofacial(CMF)reconstruction is a challenging clinical dilemma.It often necessitates skin replacement in the form of autologous graft or flap surgery,which differ from one another based on hypodermal/dermal ...Craniomaxillofacial(CMF)reconstruction is a challenging clinical dilemma.It often necessitates skin replacement in the form of autologous graft or flap surgery,which differ from one another based on hypodermal/dermal content.Unfortunately,both approaches are plagued by scarring,poor cosmesis,inadequate restoration of native anatomy and hair,alopecia,donor site morbidity,and potential for failure.Therefore,new reconstructive approaches are warranted,and tissue engineered skin represents an exciting alternative.In this study,we demonstrated the reconstruction of CMF full-thickness skin defects using intraoperative bioprinting(IOB),which enabled the repair of defects via direct bioprinting of multiple layers of skin on immunodeficient rats in a surgical setting.Using a newly formulated patient-sourced allogenic bioink consisting of both human adipose-derived extracellular matrix(adECM)and stem cells(ADSCs),skin loss was reconstructed by precise deposition of the hypodermal and dermal components under three different sets of animal studies.adECM,even at a very low concentration such as 2%or less,has shown to be bioprintable via droplet-based bioprinting and exhibited de novo adipogenic capabilities both in vitro and in vivo.Our findings demonstrate that the combinatorial delivery of adECM and ADSCs facilitated the reconstruction of three full-thickness skin defects,accomplishing near-complete wound closure within two weeks.More importantly,both hypodermal adipogenesis and downgrowth of hair follicle-like structures were achieved in this two-week time frame.Our approach illustrates the translational potential of using human-derived materials and IOB technologies for full-thickness skin loss.展开更多
Ligation of T cell receptor （TCR） alone is insufficient to induce full activation of T lymphocytes. Additional ligand-receptor interactions （costimulation） on antigen presenting cells （APCs） and T cells are requ...Ligation of T cell receptor （TCR） alone is insufficient to induce full activation of T lymphocytes. Additional ligand-receptor interactions （costimulation） on antigen presenting cells （APCs） and T cells are required. T cell costimulation has been shown to be essential for eliciting efficient T cell responses, involving all phases during T cell development. However, the mechanisms by which costimulation affects the function of T cells still need to be elucidated. In recent years, advances have been made in studies of costimulation as potential therapies in cancer, infectious disease as well as autoimmune disease. In this review, we discussed intracellular costimulation signals that regulate T cell proliferation, cell cycle progression, cytokine production, survival, and memory development. In general, the pathway of phosphoinositide-3 kinase （PI3K）/protein kinase B （PKB, also known as Akt）/nuclear factor κB （NF-κB） might be central to many costimulatory effects. Through these pathways, costimulation controls T-cell expansion and proliferation by maintenance of survivin and aurora B expression, and sustains long-term T-cell survival and memory development by regulating the expression of bcl-2 family members. Cellular ＆ Molecular Immunology. 2008;5（4）：239-247.展开更多
Human T cell leukemia virus type 1(HTLV-1),an etio-logical factor that causes adult T cell leukemia and lym-phoma(ATL),infects over 20 million people worldwide.About 1 million of HTLV-1-infected patients develop ATL,a...Human T cell leukemia virus type 1(HTLV-1),an etio-logical factor that causes adult T cell leukemia and lym-phoma(ATL),infects over 20 million people worldwide.About 1 million of HTLV-1-infected patients develop ATL,a highly aggressive non-Hodgkin's lymphoma without an effective therapy.The pX region of the HTLV-1 viral genome encodes an oncogenic protein,Tax,which plays a central role in transforming CD4+ T lymphocytes by deregulating oncogenic signaling pathways and promoting cell cycle progression.Expression of Tax following viral entry is critical for promoting survival and proliferation of human T cells and is required for initiation of oncogenesis.Tax exhibits diverse functions in host cells,and this oncoprotein primarily targets IκB kinase complex in the cytoplasm,resulting in persistent activation of NF-κB and upregulation of its responsive gene expressions that are crucial for T cell survival and cell cycle progression.We here review recent advances for the pathological roles of Tax in modulating IκB kinase activity.We also discuss our recent observation that Tax connects the IκB kinase complex to autophagy pathways.Understanding Tax-mediated pathogenesis will provide insights into development of new therapeutics in controlling HTLV-1-associated diseases.展开更多
文摘Autophagy , an evolutionarily conserved lysosomal degradation process , has drawn an increasing amount of attention in recent years for its role in a variety of human diseases, such as cancer. Notably, autophagy plays an important role in regulating several survival and death signaling pathways that determine cell fate in cancer. To date, substantial evidence has demonstrated that some key autophagic mediators, such as autophagy-related genes (ATGs), PI3K, mTOR, p53, and Beclin-1, may play crucial roles in modulating autophagic activity in cancer initiation and progression. Because autophagy-modulating agents such as rapamycin and chloroquine have already been used clinically to treat cancer, it is conceivable that targeting autophagic pathways may provide a new opportunity for discovery and development of more novel cancer therapeutics. With a deeper understanding of the regulatory mechanisms governing autophagy, we will have a better opportunity to facilitate the exploitation of autophagy as a target for therapeutic intervention in cancer. This review discusses the current status of targeting autophagic pathways as a potential cancer therapy.
文摘Development is a sophisticated process maintained by various signal transduction pathways,including the Hedgehog(Hh)pathway.Several important functions are executed by the Hh signaling cascade such as organogenesis,tissue regeneration,and tissue homeostasis,among various others.Considering the multiple functions carried out by this pathway,any mutation causing aberrant Hh signaling may lead to myriad developmental abnormalities besides cancers.In the present review article,we explored a wide range of diseases caused by aberrant Hh signaling,including developmental defects and cancers.Finally,we concluded this mini-review with various treatment strategies for Hh-induced diseases.
文摘Targeted therapies that deliver the expected anti-tumor effects while mitigating the adverse effects are taking the cancer world by storm. The need for such therapies in non-small cell lung cancer(NSCLC), where systemic cytotoxic chemotherapies still remain the backbone of management, is felt more than ever before. Runway success of immunotherapies such as Ipilimumab for melanoma has brought excitement among oncologists. Immune-based treatments are in various stages of evaluation for NSCLC as well. Immunotherapies using strategies of antigen based or cell based vaccines, and blocking immune checkpoints are of substantial interest. Meaningful clinical responses are yet to be reaped from these new treatment modalities.
文摘Accelerated partial breast irradiation (APBI) has been proposed as an alternative to whole breast radiotherapy in select patients undergoing post lumpectomy radiation therapy as part of a breast conserving approach. This comprehensive review attempts to assess the current literature and identify appropriate patients as well as supportive data.
文摘For biliary tract carcinoma(BTC),complete surgical resection of tumor is only feasible in a minority of patients,and the treatment options for patients with unresectable or metastatic disease are limited.Advances in cancer immunology have led to identification of tumor-infiltrating immune cells as indicators of prognosis and response to treatment in BTC.This has also facilitated development of immunotherapy that focuses on enhancing the immune system against biliary tumors.This includes peptide- and dendritic cell-based vaccines that stimulate in-vivo immune responses against tumorspecific antigens.Adoptive immunotherapy,which entails the ex-vivo expansion of tumor-infiltrating immune cells for subsequent reintroduction,and cytokinebased therapies have been developed in BTC.Clinical studies indicate that this type of therapy is generally well tolerated.Combination therapy with dendritic cell-based vaccines and adoptive immunotherapy has shown particularly good potential.Emerging strategies through discovery of novel antigen targets and by reversal of tumor-associated immunosuppression are expected to improve the efficacy of immunotherapy in BTC.Collaborative efforts by integration of targeted immunotherapeutics with molecular profiling of biliary tumor will hopefully make a positive impact on advancing towards the goal of developing precision treatment of patients with this highly lethal disease.
文摘The primary malignancies of the biliary tract, cholangio-carcinoma and gallbladder cancer, often present at an advanced stage and are marginally sensitive to radiation and chemotherapy. Accumulating evidence indicates that molecularly targeted agents may provide new hope for improving treatment response in biliary tract carcinoma(BTC). In this article, we provide a critical review of the pathogenesis and genetic abnormalities of biliary tract neoplasms, in addition to discussing the current and emerging targeted therapeutics in BTC. Genetic studies of biliary tumors have identified the growth factors and receptors as well as their downstream signaling pathways that control the growth and survival of biliary epithelia. Target-specific monoclonal antibodies and small molecules inhibitors directed against the signaling pathways that drive BTC growth and invasion have been developed. Numerous clinical trials designed to test these agents as either monotherapy or in combination with conventional chemotherapy have been completed or are currently underway. Research focusing on understanding the molecular basis of biliary tumorigenesis will continue to identify for targeted therapy the key mutations that drive growth and invasion of biliary neoplasms. Additional strategies that have emerged for treating this malignant disease include targeting the epigenetic alterations of BTC and immunotherapy. By integrating targeted therapy with molecular profiles of biliary tumor, we hope to provide precision treatment for patients with malignant diseases of the biliary tract.
文摘Autophagy, a cellular process of "self-eating" by which intracellular components are degraded within the lysosome, is an evolutionarily conserved response to various stresses. Autophagy is associated with numerous patho-physiological conditions, and dysregulation of autophagy contributes to the pathogenesis of a variety of human diseases including cancer. Depending on context, activation of autophagy may promote either cell survival or death, two major events that determine pathological process of many illnesses. Importantly, the activity of autophagy is often associated with apoptosis, another critical cellular process determining cellular fate. A better understanding of biology of autophagy and its implication in human health and disorder, as well as the relationship between autophagy and apoptosis, has the potential of facilitating the development of autophagy -based therapeutic interventions for human diseases such as cancer.
文摘Despite various advances in cancer research,the incidence and mortality rates of malignant diseases have remained high.Accurate risk assessment,prevention,detection,and treatment of cancer tailored to the individual are major challenges in clinical oncology.Artificial intelligence(AI),a field of applied computer science,has shown promising potential of accelerating evolution of healthcare towards precision oncology.This article focuses on highlights of the application of data-driven machine learning(ML)and deep learning(DL)in translational research for cancer diagnosis,prognosis,treatment,and clinical outcomes.MLbased algorithms in radiological and histological images have been demonstrated to improve detection and diagnosis of cancer.DL-based prediction models in molecular or multi-omics datasets of cancer for biomarkers and targets enable drug discovery and treatment.ML approaches combining radiomics with genomics and other omics data enhance the power of AI in improving diagnosis,prognostication,and treatment of cancer.Ethical and regulatory issues involving patient confidentiality and data security impose certain limitations on practical implementation of ML in clinical oncology.However,the ultimate goal of application of AI in cancer research is to develop and implement multi-modal machine intelligence for improving clinical decision on individualized management of patients.
基金funded by the Penn State Cancer Institute—Highmark Seed Grant (SRK)College of Engineering Multidisciplinary Grant,and Grace Woodward Grant (SRK).
文摘Objective and Impact Statement.Simultaneous imaging of ultrasound and optical contrasts can help map structural,functional,and molecular biomarkers inside living subjects with high spatial resolution.There is a need to develop a platform to facilitate this multimodal imaging capability to improve diagnostic sensitivity and specificity.Introduction.Currently,combining ultrasound,photoacoustic,and optical imaging modalities is challenging because conventional ultrasound transducer arrays are optically opaque.As a result,complex geometries are used to coalign both optical and ultrasound waves in the same field of view.Methods.One elegant solution is to make the ultrasound transducer transparent to light.Here,we demonstrate a novel transparent ultrasound transducer(TUT)linear array fabricated using a transparent lithium niobate piezoelectric material for real-time multimodal imaging.Results.The TUT-array consists of 64 elements and centered at~6 MHz frequency.We demonstrate a quad-mode ultrasound,Doppler ultrasound,photoacoustic,and fluorescence imaging in real-time using the TUT-array directly coupled to the tissue mimicking phantoms.Conclusion.The TUT-array successfully showed a multimodal imaging capability and has potential applications in diagnosing cancer,neurological,and vascular diseases,including image-guided endoscopy and wearable imaging.
基金Supported by AA and MDSIF research grant to Pu JJ,No.146818American Cancer Society grant to Pu JJ,No.124171-IRG-13-043-02a Pennsylvania State University College of Medicine research grant to Pu JJ
文摘Acquired bone marrow failure diseases(ABMFD) are a class of hematopoietic stem cell diseases with a commonality of non-inherited disruption of hematopoiesis that results in pancytopenia. ABMFDs also are a group of heterogeneous diseases with different etiologies and treatment options. The three most common ABMFDs are aplastic anemia, myelodysplastic syndrome, and paroxysmal nocturnal hemoglobinuria. Stem cell transplantation is the only treatment that can cure these diseases. However, due to high therapy-related mortality, stem cell transplantation has rarely been used as a first line treatment in treating ABMFD. With the advance of personalized medicine and precision medicine, various novel cellular therapy strategies are in trial to increase the efficiency and efficacy of ABMFD treatment. This article aims to review current available stem cell transplantation protocols and promising cellular therapy research in treating ABMFD.
基金This project was supported by grants from the National Natural Science Foundation of China （No. 81072146 and No. 81101913）, Natural Science Foundation of Jiangsu Province of China （BK2010224） and Natural Science Foundation of Jiangsu Provincial Colleges and Universities （No. 08KJB310010）.
文摘Objective To provide a summary of the relationship between the eEF-2/eEF-2 kinase pathway and each phase of malignant neoplasms. The specific importance of this relationship in understanding and treating cancer was also explored. Data sources The data used in this review were mainly obtained from the articles listed in HighWire and PubMed in English. The search terms were ＂eEF-2 kinase＂, ＂oncogenesis＂, and ＂tumor progression＂. Study selection This review relates the observation that the overexpression of eEF-2 kinase is seen in cancer, and highlights that it has emerged as promoting the development of many malignant phenotypes when unregulated. This includes increasing the replicative potential of cells, angiogenesis, invasion and metastasis, and evasion of apoptosis. Results eEF-2 kinase is a structurally and functionally unique protein kinase. The increased activity of this protein in cancer cells is a protective mechanism to allow tumor growth and evolution, and resist cell death through the eEF-2/eEF-2 kinase pathway, but it also makes a potential target for therapy. Conclusion eEF-2 kinase fills critical niches in the life of a cancer cell and the eEF-2/eEF-2 kinase pathway is a key biochemical sensor.
基金supported by National Institutes of Health Award R01DE028614,R56HL157190,R21AR082668,and R01AR078743,and 2236 CoCirculation2 of TUBITAK award 121C359.
文摘Craniomaxillofacial(CMF)reconstruction is a challenging clinical dilemma.It often necessitates skin replacement in the form of autologous graft or flap surgery,which differ from one another based on hypodermal/dermal content.Unfortunately,both approaches are plagued by scarring,poor cosmesis,inadequate restoration of native anatomy and hair,alopecia,donor site morbidity,and potential for failure.Therefore,new reconstructive approaches are warranted,and tissue engineered skin represents an exciting alternative.In this study,we demonstrated the reconstruction of CMF full-thickness skin defects using intraoperative bioprinting(IOB),which enabled the repair of defects via direct bioprinting of multiple layers of skin on immunodeficient rats in a surgical setting.Using a newly formulated patient-sourced allogenic bioink consisting of both human adipose-derived extracellular matrix(adECM)and stem cells(ADSCs),skin loss was reconstructed by precise deposition of the hypodermal and dermal components under three different sets of animal studies.adECM,even at a very low concentration such as 2%or less,has shown to be bioprintable via droplet-based bioprinting and exhibited de novo adipogenic capabilities both in vitro and in vivo.Our findings demonstrate that the combinatorial delivery of adECM and ADSCs facilitated the reconstruction of three full-thickness skin defects,accomplishing near-complete wound closure within two weeks.More importantly,both hypodermal adipogenesis and downgrowth of hair follicle-like structures were achieved in this two-week time frame.Our approach illustrates the translational potential of using human-derived materials and IOB technologies for full-thickness skin loss.
基金The project was funded,in part,under grants from the Pennsylvania Department of Health and St.Baldrick's Foundation (J.Song)
文摘Ligation of T cell receptor （TCR） alone is insufficient to induce full activation of T lymphocytes. Additional ligand-receptor interactions （costimulation） on antigen presenting cells （APCs） and T cells are required. T cell costimulation has been shown to be essential for eliciting efficient T cell responses, involving all phases during T cell development. However, the mechanisms by which costimulation affects the function of T cells still need to be elucidated. In recent years, advances have been made in studies of costimulation as potential therapies in cancer, infectious disease as well as autoimmune disease. In this review, we discussed intracellular costimulation signals that regulate T cell proliferation, cell cycle progression, cytokine production, survival, and memory development. In general, the pathway of phosphoinositide-3 kinase （PI3K）/protein kinase B （PKB, also known as Akt）/nuclear factor κB （NF-κB） might be central to many costimulatory effects. Through these pathways, costimulation controls T-cell expansion and proliferation by maintenance of survivin and aurora B expression, and sustains long-term T-cell survival and memory development by regulating the expression of bcl-2 family members. Cellular ＆ Molecular Immunology. 2008;5（4）：239-247.
基金supported by a grant from National Institute of Health to H.Cheng.
文摘Human T cell leukemia virus type 1(HTLV-1),an etio-logical factor that causes adult T cell leukemia and lym-phoma(ATL),infects over 20 million people worldwide.About 1 million of HTLV-1-infected patients develop ATL,a highly aggressive non-Hodgkin's lymphoma without an effective therapy.The pX region of the HTLV-1 viral genome encodes an oncogenic protein,Tax,which plays a central role in transforming CD4+ T lymphocytes by deregulating oncogenic signaling pathways and promoting cell cycle progression.Expression of Tax following viral entry is critical for promoting survival and proliferation of human T cells and is required for initiation of oncogenesis.Tax exhibits diverse functions in host cells,and this oncoprotein primarily targets IκB kinase complex in the cytoplasm,resulting in persistent activation of NF-κB and upregulation of its responsive gene expressions that are crucial for T cell survival and cell cycle progression.We here review recent advances for the pathological roles of Tax in modulating IκB kinase activity.We also discuss our recent observation that Tax connects the IκB kinase complex to autophagy pathways.Understanding Tax-mediated pathogenesis will provide insights into development of new therapeutics in controlling HTLV-1-associated diseases.
